Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases

• Published in: Journal of allergy and clinical immunology Vol. 154; no. 5; pp. 1204 - 1215.e9
• Main Authors: van Straalen, Kelsey R., Kirma, Joseph, Yee, Christine M., Bugada, Luke F., Rizvi, Syed M., Wen, Fei, Wasikowski, Rachael, Fox, Jennifer, Do, Tran H., Schuler, Charles F., Xing, Enze, MacLeod, Amanda S., Harms, Paul W., Berthier, Celine C., Kahlenberg, J. Michelle, Leung, Monica W.L., Tsoi, Lam C., Gudjonsson, Johann E.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2024
• Subjects: Adult; Aged; bulk RNA sequencing; Cytokines - genetics; Cytokines - immunology; dyshidrotic eczema; Eczema - classification; Eczema - genetics; Eczema - immunology; Female; Humans; Male; Middle Aged; molecular classification; palmoplantar psoriasis; Palmoplantar pustulosis; Psoriasis - classification; Psoriasis - genetics; Psoriasis - immunology; RNA-Seq; Skin - immunology; Skin - pathology; Transcriptome; transcriptomics; CXCL; dyshidrotic eczema; Palmoplantar pustulosis; DEG; GO; MHC; bulk RNA sequencing; palmoplantar psoriasis; CCL; molecular classification; MMP; PPP; RNA-Seq; FDR; transcriptomics; DPE; palmPP; FC
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2024.07.017

[Display omitted] Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non–pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE). We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis. We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples. Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell–associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity. A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.